Most Common PEOModified PLAA Micelles Investigated for Drug Delivery

Drug Incorporation Method

Chemical conjugation®

Physical encapsulation

PLAA Block

Incorporated Drug

Cyclophosphamid

Latest Reported Phase of Progress

Development

References

PLAA Block

Incorporated Drug

Cyclophosphamid

Latest Reported Phase of Progress

Development

References

sulfide

P(Asp)

Doxorubicin

Development

12, 18, 22, 98, 100

PHEA

Methotrexate

Development

33, 87, 90

PBLA

Doxorubicin

Development

13, 94, 95

P(Asp)-DOX

Doxorubicin

Clinical trials phase II

12, 17, 21, 23, 100

PBLG

Doxorubicin

Development

133

PPBA

Paclitaxel

Clinical trials phase I

24

PBL-C16(Asp)

KRN-5500

Development

65, 110

PBLA

Camptothecin

Development

113

P(n-butyl-l-Asp)

Camptothecin

Development

113

P(lauryl-l-Asp)

Camptothecin

Development

113

P(methylnaphtyl-l-

Camptothecin

Development

113

Development Development Development Development Clinical trials phase I

Asp)

PBLA Amphotericin B

PHSA Amphotericin B

PBLA Indomethacin

Electrostatic complexationc P(Asp) Cisplatin

P(Glu) Cisplatin a Most common chemical structures shown in Figure 18.5. b Most common chemical structures shown in Figure 18.6. c Most common chemical structures shown in Figure 18.7.

Development Development Development Development Clinical trials phase I

For the synthesis of PEO-b-PLAA block copolymers, a-methoxy-u-amino PEO has been used as the initiator. Synthesis of PEO-b-poly(b-benzyl-L-aspartate) (PEO-b-PBLA) and PEO-b-poly[s-(benzyloxycarbonyl)-L-lysine] (PEO-b-PBLL) from polymerization of b-benzyl-L-aspartate-N-carboxyanhydride (BLA-NCA) and N-carboxyanhydride of s-(benzyloxycarbonyl)-L-lysine (BLL-NCA), respectively, using a-methoxy-u-amino PEO as initiator has been reported.49 When primary amines are used as initiators, the NCA polymerization may proceed by two different mechanisms: amine mechanism and activated monomer (AM) mechanism (Figure 18.2A and Figure 18.2B).48,50 The amine mechanism is a nucleophilic ring-opening chain-growth process where the polymer linearly grows with monomer conversion (Figure 18.2A). In the AM mechanism, NCA will be deprotonated, forming a nucleophile that initiates chain growth (Figure 18.2B). Polymerization by the AM mechanism may lead to side reactions. Besides, the initiator will not be part of the final product. In a given polymerization process, the system can

II /N^CHX Nucleophile H O\

FIGURE 18.1 General scheme for the synthesis of PEO-b-PLAA-based block copolymers by ring-opening polymerization of a-amino acid-N-carboxyanhydrides (NCAs).

nNCA

N OH

n NH2

nCO2

RH N

R-NH3

RH N

RH N

RH N

ON O

OR N-aminoacyl NCA

H+ transfer

-CO2

ON O

OR N-aminoacyl NCA

H+ transfer

Reaction with NCA

-CO2

Further

FIGURE 18.2 (a) Amine mechanism and (b) activated monomer (AM) mechanism of NCA polymerization. (From Deming, T. J., Advanced Drug Delivery Reviews, 54, 8, 2002. With permission.)

alternate between the amine and AM mechanisms. Because a propagation step for one mechanism is a side reaction for the other and vice versa, block copolymers prepared from the NCA method using amine initiators have structures different from those predicted by monomer feed compositions and, most likely, have considerable homopolymer contamination.

To avoid side reactions, transition metal initiators have been developed51-55 that use transition metal complexes as the end groups to control the addition of each NCA monomer to the polymer chain ends. However, the presence of chain-transfer reactions prevents the preparation of high molecular weight PLAAs by this process.

Living polymerization is a relatively novel method to prepare PLAA that has been developed to overcome the mentioned limitations of existing methods (Figure 18.3).56-58 In this method, the transition metal initiator activates the monomers and forms covalent active species that permit the formation of polypeptides via the living polymerization of NCAs. The metals react identically with NCA monomers to form metallacyclic complexes by oxidative addition across the anhydride bond of NCA. The AB diblock, PEO-b-poly(L-lysine) (PEO-b-P(L-Lys)), ABA triblock, poly(g-benzyl-L-glutamate)-b-PEO-b-poly(y-benzyl-L-glutamate) (PBLG-b-PEO-b-PBLG) copolymers, and diblock copolymers of poly(methyl acrylate)-b-(PBLG) of high molecular weights have been synthesized by living polymerization mechanism.50,56,59

Alternatively, PEO can be coupled to PLAA after the polymerization of PLAA. For instance, poly(L-histidine) (P(L-His)) has been synthesized by base-initiated ROP of protected NCA of L-His and coupled to carboxylated PEO to form PEO-b-P(L-His) via an amide linkage using dicyclohexyl carbodiimide (DCC) and N-hydroxysuccinimide (NHS).60

NCA O

O proton migration

Nn H

O proton migration

Nn H

HN O

proton migration

proton migration

HN C

HN C

FIGURE 18.3 Living polymerization of NCA.

PEO-co-P(L-aspartic acid) (PEO-co-P(L-Asp))-bearing amine groups on the P(L-Asp) block have been synthesized by the melt polycondensation of N-(benzyloxycarbonyl)-L-aspartic acid anhydride (N-CBZ-l-ASP anhydride) and low molecular weight PEO. The product was an alternating copolymer having reactive amine groups on the P(L-Asp) residue. The backbone was linked by ester bond that is more biodegradable than the amide bond between PEO and P(L-Asp).61

Preparation of micelle-forming PEO-b-PLAA-based block copolymers with poly(leucine), poly(tyrosine), poly(phenylalanine) (PPA), and a composition peptide, i.e., poly(phenylalanine-co-leucine-co-tyrosin-co-tryptophan) P(FLYW), as the core forming block through solid phase peptide synthesis has also been reported.62 Methoxy PEO-b-PLAA dendrimers have also been prepared by the liquid phase peptide synthesis and used in drug delivery.63

18.3 MICELLIZATION OF PEO-b-PLAA BLOCK COPOLYMERS

Assembly of micelle-forming PEO-b-PLAA block copolymers through one of the following methods has been reported.

18.3.1 Dialysis Method

In this method, block copolymer is dissolved in a water miscible organic solvent first. Then, this solution is dialyzed against water. The semi-permeable membrane keeps the micelles inside the dialysis bag, but it allows removal of organic solvent. Gradual replacement of the organic solvent with water, i.e., the non-solvent for the core-forming block, triggers self-association of block copolymers (Figure 18.4A).13'35'40'64'65

18.3.2 Solvent Evaporation Method

In this process, the polymer is dissolved in a volatile organic solvent. The organic solvent is then removed completely by evaporation (usually under reduced pressure), leading to the formation of polymer films. Next, this film is reconstituted in an aqueous phase by vigorous shaking.36,66 The solvent evaporation method of micellization cannot be utilized for block copolymers having large hydrophobic segments because the polymer film cannot be reconstituted easily in an aqueous phase for those structures (Figure 18.4B).

18.3.3 Co-Solvent Evaporation Method

In this approach, polymer is dissolved in a volatile water miscible organic solvent such as methanol. Then self-assembly is triggered by the gradual addition of aqueous phase (non-solvent for the core-forming block) to the organic phase. This step is followed by the evaporation of the organic co-solvent (Figure 18.4C).33,34

Polymer is dissolved in the organic solvent

Gradual displacement of organic solvent with water through dialysis

Gradual mixing with water

Gradual mixing with water

Solvent evaporation/film formation

FIGURE 18.4 Micellization of PEO-b-PLAA-based block copolymers through (A) dialysis, (B) solvent evaporation, and (C) co-solvent evaporation methods.

18.4 RATIONAL DESIGN AND FUNCTIONAL PROPERTIES OF PEO-b-PLAA MICELLES IN DRUG DELIVERY

18.4.1 The PEO Shell

PEO has a safe history of application as a pharmaceutical ingredient for the design of non-immuno-genic peptides, carriers, or biomedical surfaces.67'68 In PEO-b-PLAA, the presence of hydrophilic PEO chains introduces amphiphilicity, leading to the self-assembly of block copolymer and formation of association colloids. The PEO shell is expected to induce steric repulsive forces and to stabilize the colloidal interface against aggregation or absorption of proteins to the carrier as well.10,69-71 As a result, the colloidal carrier will stay within the appropriate size range and surface properties that can avoid uptake by RES. A major barrier against targeted tumor delivery by colloidal carriers is the non-specific uptake and clearance of the carrier from the blood stream by RES. Avoiding RES will prolong the circulation of polymeric micelles in blood, providing more chance for the extravasation of the carrier at sites with leaky vasculature (e.g., solid tumors).

The extent of steric stabilization is found to be dependent on the length and density of the PEO

20 72_74

chain on the surface of colloidal carriers. , Elongation of the PEO chain or an increase in the aggregation number of PEO-b-PLAA micelles may lead to the reduced chance of micellar aggregation and longer circulation time in blood and a higher probability of passive targeting to the tumor site for polymeric micelles.10 The same parameter may reduce the adherence and interaction of the polymeric micelles with target cells.75

18.4.2 The PLAA Core

Chemical flexibility of the PLAA structure as the core-forming block is the primary advantage of the PEO-b-PLAA-based polymeric micelles. Existence of several functional groups on a PLAA block provides a number of sites for the attachment of drugs, drug compatible moieties, or charged therapeutics to a single polymeric backbone in micelle-forming PEO-b-PLAA block copolymers. This may lead to a lower dose of administration for drugs that are chemically conjugated to the PLAA block of PEO-b-PLAA. On the other hand, the diversity of functional groups in a PLAA chain (amino, hydroxyl, and carboxylic groups) allows conjugation of different chemical entities to the polymeric backbone and provides an opportunity for the design of polyion complex and/or pH responsive polymeric micelles. Finally, through changes in the chemical structure of the PLAA block, it will also be possible to fine tune the structure of PEO-b-PLAA micelles to achieve optimal properties for drug targeting.4 From a pharmaceutical point of view, PEO-b-PLAA micelles are considered advantageous over PEO-b-poly(ester)s because they can easily be reconstituted after freeze-drying and do not need lyoprotection.

The most effort for the production of PEO-b-PLAA micellar delivery systems has been focused on the application of P(L-Asp), poly(L-glutamic acid) (P(l-GIu)), and P(L-Lys)-based polymers (Table 18.1, Figure 18.5 through 18.7). This is owed to the presence of free carboxyl and amino groups that makes these structures useful for the chemical conjugation and electrostatic complexa-tion of drugs and DNA to the PLAA block.76

A major concern for the application of PLAA-based pharmaceuticals is the possibility of immu-nogenic reactions and long-term accumulation and toxicity by these agents. Unfortunately, the information on the biocompatibility and biodegradability of PLAAs is limited.77,78 Nevertheless, the results of ongoing clinical trials in Japan on PEO-PLAA-based micelles for the delivery of DOX, PTX, and CDDP is expected to provide more information on the safety of these structures.

18.4.3 Micellar Dimensions

PEO-b-PLAA micelles developed to date are mostly in a diameter range of 10-100 nm.79 At this specific size range, PEO-b-PLAA micelles are expected to be big enough to avoid glomerular

PEO-fa-P(Asp)-DOX CH3-0-CH2-CH

NH^C-CH-NH

C CH2 CH NH

CO I

O OH

O OH

OH O OH

OH O OH

PEO-fa-PHEA-MTX CH

O CH2 CH2

HOOC CH2 CH2 CO O CH2 CH2 NH CO

CO NH CH2 CH2 OH

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